NEW YORK (GenomeWeb News) – Chromatin remodeling and ubiquitin ligase genes are among those most frequently mutated in an aggressive endometrial cancer subtype called serous endometrial cancer, according to a new study.
For the analysis, researchers from the National Human Genome Research Institute's Cancer Genetics Branch and elsewhere did whole-exome sequencing on 13 serous endometrial tumors as well as matched normal tissue samples. The study, appearing online yesterday in Nature Genetics, led them to a set of suspicious genes that were mutated in multiple tumors or found in frequently altered functional groups. Among them: members of ubiquitin ligase and chromatin modification pathways.
"This discovery really changes our understanding of some of the genetic alterations that may contribute to this disease," senior author Daphne Bell, head of the reproductive cancer genetics section in NHGRI's Cancer Genetics Branch, said in a statement.
Endometrial cancer, a cancer that affects the tissue that lines the uterus, is typically classified into three main histology-based subtypes. The most common of these is the endometrioid subtype, which has a five-year survival rate of around 91 percent and represents the majority of endometrial cancer cases.
The other endometrial cancer subtypes — clear-cell endometrial cancer and serous endometrial — tend to be more aggressive, with five-year survival rates of 65 percent and 45 percent, respectively, authors of the new study explained.
For this analysis, the team focused mainly on serous endometrial cancer — a subtype that generally represents less than 10 percent of endometrial cancer diagnoses, but which contributes substantially to the tally of fatal endometrial cancer cases. In a statement, Bell noted that serous endometrial tumors account for up to 39 percent of endometrial cancer deaths.
For their exome sequencing analyses of tumor and matched normal samples from 13 women with serous endometrial cancer, the researchers first captured protein-coding sequencing from each tumor-normal pair using Agilent SureSelect kits. They then sequenced each exome to a mean depth of nearly 103-fold coverage over some 90 percent of the sequence targeted using Illumina's GAIIx platform.
Analyses of the exomes uncovered more than 1,500 somatic mutations affecting coding sequences, along with almost two-dozen splice site mutations.
One tumor had especially high mutation levels and a distinct mutation signature, prompting researchers to classify it as hypermutable. In the remaining 12 tumors, they detected more than 500 somatic mutations, including 109 synonymous, 321 non-synonymous mutations, and nine splice junction mutations that were subsequently verified by Sanger sequencing.
The team then screened 40 more serous endometrial tumors for mutations to nine genes that had contained potentially pathogenic alterations in at least two of the exomes assessed initially.
Along with recurrent mutations to genes that have been implicated in endometrial cancer in the past (TP53, PIK3CA, and PPP2R1A), researchers saw an over-representation in alterations affecting CHD4, FBXW7, and SPOP.
Those three genes — which have been linked to processes that include chromatin assembly, DNA damage response, tumor suppression and/or the function of ubiquitin ligase complexes — were mutated in 40 percent of all the serous tumors tested.
And mutations in CHD4, FBXW7, and SPOP turned up in endometrial tumors from other subtypes, too. When they did targeted testing on 23 clear-cell tumors, 67 endometrioid tumors, and 18 tumors classified as having mixed histology, they found mutations in these genes between 15 percent and 26 percent of the time.
Likewise, 11 chromatin remodeling genes, including CHD4, fell out of their functional analysis of genes mutated in the discovery phase of the study. Representatives from that 11-gene set were mutated in 37 percent of serous tumors and 22 percent of clear-cell tumors screened.
All told, the study authors reported that half of serous endometrial tumors and more than one-third of clear-cell tumors tested had alterations affecting genes in chromatin remodeling or ubiquitin ligase complex pathways.
Still, they cautioned that more work will be needed to find lower frequency mutations that might contribute to the disease.
"[I]t is important to acknowledge that our discovery screen is underpowered to detect all somatically mutated genes that drive serous tumors," the study authors noted, adding that "[m]assively parallel sequencing of additional cases will undoubtedly yield deeper insights into the mutational landscape of serous endometrial cancer."